This application seeks renewal of R37-AG10880, Glucose Regulation and Memory in Alzheimer's Disease. Our continuing focus is periptieral insulin resistance (i.e., high plasma insulin levels and reduced insulin effectiveness) as an antecedent or risk factor for Alzheimer's disease (AD). A key hypothesis posits that a specific form of insulin resistance, one that is associated with hypertension (hereafter, termed hypertension-associated insulin resistance or HAIR), interferes with peripheral and brain vascular function, and p-amyloid (AP) regulation. We hypothesize that HAIR creates a pathophysiological foundation for AD, and that this foundation is laid down in mid-life, a timeframe which allows for early detection and treatment. To test these hypotheses we will use a highly sensitive model developed in our current funding cycle: ingestion of a high saturated fat/high glycemic index diet (HSF/HGI) for 4 weeks, a time sufficient to induce mild metabolic changes characteristic of HAIR in a safe manner. We provide preliminary data supporting the validity and safety of this model. We will also investigate beneficial effects of a low saturated fat/low glycemic index diet (LSF/LGI) on metabolic and AD markers. Our preliminary data suggest that improving insulin resistance through this diet enhances cognitive function for normal and memory-impaired adults. Participants will include four groups of middle-aged (45-65 yr) adults: 1) pre-hypertensive (systolic blood pressure ranging from 120-139 mm/Hg) with insulin resistance (homeostasis model assessment of insulin resistance or HOMA-IR > 3.7), a group we term pHAIR; 2) pre-hypertensive without insulin resistance; 3) normotensive with insulin resistance; and 4) normotensive without insulin resistance. Endpoints will be cognition, CSF and plasma Ap levels, lipoprotein/lipid levels, and cerebral blood flow (arterial spin labeling perfusion MRI). We hypothesize that adults with pHAIR will show abnormal AD biomarker patterns, cerebral blood flow, and cognition, and that diet interventions will produce the greatest changes in these adults.The proposed studies will provide evidence that pHAIR is associated with a pathological midlife pattern ofAD markers and provide evidence for dietary strategies that may benefit patients who have mild cognitive impairment or AD. RELEVANCE (See instructions): The proposed studies will test the hypothesis that diet modulates cognitive and biologic markers of Alzheimer's disease, and that a specific form of insulin-resistance, characterized by hypertension, is associated with abnormal patterns of these markers in midlife. Identification of a clear metabolic risk profile in middle age may offer an opportunity for preventative strategies. The proposed study will address one such strategy; consumption of a low saturated fat/low glycemic index diet.